Head injury kills more persons under the age of 44 than all other diseases combined and accounts for 500,000 hospitalizations each year in which 70,000 are severe cases and some 2000 persons are left in a persistent vegetative state. These injures cost over a billion dollars for hospitalized patients alone. Moreover, some 165,000 children will be hospitalized, 16,000 of which have moderate to severe symptoms. It can be concluded that head injuries are a very serious health problem in the United States alone.
In both humans and in animal models, the sequence of events following head trauma, referred to as post-concussion syndrome can be divided into two phases (1). The first phase is an acute phase consisting of the first six hours during which the organism may be lethargic but functional. During this phase, intracranial pressure is less than 15 mmHg. A second phase begins at six hours and extends for up to five days during which the organism may become comatose. In this second phase, intracranial pressure increases to more than 20 mmHg at 24 hours and it may approach 40 mmHg in an animal model of closed head injury. During this second phase, sometimes referred to as the secondary injury, very serious irreversible brain damage can occur which has to date proven to be intractable to treatment in clinical settings.
Treatments currently used for the above discussed injuries all have serious limitations and are potentially debilitating because of the side effects resulting from the administration thereof. The most important requirement of these treatments is to reduce the rising intracranial pressure as soon as possible. Currently, therapy consists of intravenous infusion of hypertonic mannitol solution. The hypertonic solution was originally believed to act by causing an increase in the osmotic gradient between blood and brain thus drawing water from the edematous brain so as to reduce the dangerously high intracranial pressure (2).
Mannitol may also function by reducing ventricular cerebral spinal fluid. Very recently, it has been shown that mannitol is a free-radical scavenger and may be effective in this mode against rising intracranial pressure by reducing inflammatory oxygen free-radicals, a proposed mechanism for the increased brain water content (4). A problem exists with the use of mannitol in such treatments because such treatment can lead to fluid and electrolyte disturbances. If serum osmolality increases above 320 mosmol/liter, renal failure can result.
Other treatments that have been used in the past consist of unreliable barbiturate therapy which additionally has the potential for causing arterial hypotension, and corticosteroid therapy which has proven to be ineffective in reducing the high intracranial pressure resulting from moderate concussion. Neither of the aforementioned treatments is able to reliably improve the outcome (2).
It can be concluded that despite recent technological developments that enable physicians to closely monitor head injured patients, treatment of the most serious complication of head injury which is the edematous brain still relies on clinically questionable methods. Such methods are now more than 30 years old and still have significant limitations and toxicities.
Human adrenocorticotropin hormone (ACTH) is a peptide of 39 amino acid residues. Ovine, porcine, and bovine ACTH differ from human ACTH only at the amino acid positions 25,31, and 33. The loss of one amino acid from the N-terminal end of the molecule by hydraulic cleavage results in complete loss of biological activity. In contrast, a number of amino acids may be split off of the C-terminal end with no effect on potency. A 20-amino acid peptide (sequence 1-20) retains the activity of the parent hormone.
In vivo, ACTH stimulates the human adrenocortex to secrete cortisol, corticosterone, aldosterone, and a number of weekly androgenic substances. Absent ACTH, the adrenocortex undergoes atrophy and the rates of secretion of cortisol and corticosterone, which are marketably reduced, do not respond to otherwise-effective stimuli.
ACTH acts to stimulate the synthesis of adrenocorticotropin hormones. ACTH controls its target tissue through the agency of cyclic AMP.
ACTH has been manufactured for commercial use as corticotropin for subcutaneous, intramuscular, or intravenous administration. The preparation is derived from the pituitaries of mammals used for food. The most important use of a ACTH as a diagnostic agent is in adrenal insufficiency. Therapeutic uses of ACTH have included the treatment of adrenocortical insufficiency and other disorders that are responsive to glucocorticoids. Also, ACTH stimulates secretion of mineral corticoids such that it may cause acute retention of salt and water.
Fragments of ACTH have been studied, the studies being most recently described by DeWeid (3).